4-methyl-5-(2-(4-phenylpiperazin-1-yl)ethyl)thiazole derivatives their method of preparation and the pharmaceutical compositions in which they are present

ABSTRACT

The present invention relates to novel 4-methyl-5-[2-(4-phenylpiperazin-1-yl)ethyl]thiazole derivatives of the general formula ##STR1## in which R is selected from a hydrogen atom, an alkyl radical having from 2 to 7 carbon atoms and an aralkyl radical of which the aryl moiety preferably consists of phenyl and of which the alkyl moiety has from 1 to 4 carbon atoms, and to the pharmaceutically acceptable salts of these derivatives. 
     It further relates to a method of preparing these products and to pharmaceutical compositions in which they are incorporated. 
     These derivatives are applied especially in the preparation of drugs intended for the treatment of functional dysuria associated with hyperactivity of the α-adrenergic sympathetic nervous system.

The present invention relates, by way of novel products, to the productsof the following general formula: ##STR2## in which R is selected from ahydrogen atom, an alkyl radical having from 2 to 7 carbon atoms and anaralkyl radical of which the aryl moiety preferably consists of phenyland of which the alkyl moiety has from 1 to 4 carbon atoms, it beingpossible for said products to take the form of pharmaceuticallyacceptable salts.

In formula (I), the alkyl or aralkyl radicals can have a linear orbranched chain.

An alkyl group having from 2 to 7 carbon atoms is, for example, ethyl,propyl, isopropyl, butyl, tert-butyl, pentyl, neopentyl, isopentyl,hexyl or heptyl.

An aralkyl radical is, for example, benzyl, ethylphenyl, propylphenyl ormethylnaphthyl, preferably benzyl.

The salts of the products of formula (I) are obtained in known manner bybringing a product of formula (I) into contact with an appropriateamount of a pharmaceutically acceptable acid such as, for example, amineral acid like hydrochloric acid or sulfuric acid, or an organic acidlike citric, tartaric, maleic or methanesulfonic acid.

4-Methyl-5-[2-(4-phenylpiperazin-1-yl)ethyl]-thiazole is described inFrench patent application no. 2 594 335.

Derivatives of this compound have also been described in thepublications Acta-Pol. Pharm. 40(2), page 159 and Pol. Pl. 78 185, 19May 1975. However, the products of formula (I) and their salts havenever been described in the literature.

The present invention further relates to a method of preparing productsof formula (I), said method consisting in reacting, with one equivalentof 4-methyl-5-β-chloroethylthiazole, either two equivalents of4-phenylpiperazine substituted in the 2-position on the phenyl by agroup OR, in which R is as defined above, or one equivalent of4-picoline and one equivalent of substituted 4-phenylpiperazine, or oneequivalent of substituted 4-phenylpiperazine and an excess of anhydroussodium carbonate, and, if desired, in converting the resulting productto one of its pharmaceutically acceptable salts. Said reaction isgenerally carried out with heating and in a solvent medium.

The present invention further relates to a pharmaceutical compositioncontaining at least one product of formula (I) as the active product, itbeing possible for said composition to be useful especially in the fieldof urology.

According to this feature, the invention also aims to cover a method ofpreparing drugs useful especially in the field of urology, whichcomprises incorporating at least one product of formula (I), as theactive product, into a pharmaceutically acceptable vehicle, excipient orcarrier.

4-Methyl-5-[2-(4-phenylpiperazin-1-yl)ethyl]-thiazole, described inFrench patent application 2 594 335, is also recommended as an activeingredient in drugs useful in the field of urology.

However, as will be demonstrated below, all the compounds according tothe present invention possess very valuable pharmacological propertiesand, in particular, have a 50% effective dose (ED₅₀) which is veryappreciably lower than that of this compound known in the prior art.

It has been discovered, unexpectedly, that the particular family of4-methyl-5-[2-(4-phenylpiperazin-1-yl)ethyl]thiazole derivativescontaining a hydroxyl or alkoxy group in the 2-position on the terminalphenyl ring have very valuable pharmacological properties and that thetoxicity of these derivatives is sufficiently low to enable them to beused in therapeutics.

The same also applies to the derivative containing a methoxy group inthe 2-position on the phenyl ring. This compound is not claimed as anovel product since it has been described in the afore-mentionedpublication ACTA Pol. Pharm. 40(2), page 159. However, the knownactivity of said compound is quite different from the activitydemonstrated by the Applicant.

It is for this reason that the invention further relates to the use ofthe compounds of aforementioned formula (I), in which the radical R isas defined above and can also be a methyl radical, in the preparation ofdrugs useful for the treatment of functional dysuria associated withhyperactivity of the α-adrenergic sympathetic nervous system.

According to a last feature, the present invention also aims to cover amethod of treating functional dysuria associated with hyperactivity ofthe α-adrenergic sympathetic nervous system, which comprisesadministering an effective amount of at least one compound of generalformula (I), in which the radical R is as defined above and can also bea methyl radical.

The invention will be illustrated in greater detail by the followingnon-limiting Examples. In these Examples, the AgNO₃ assay is a test ofproduct purity.

EXAMPLE 1

Synthesis of4-methyl-5-[2-(4-o-ethoxyphenylpiperazin-1-yl)ethyl]thiazoletrihydrochloride. Code name: B 1211. Product of formula (I) whereR=ethyl, in the form of the trihydrochloride.

1) Preparation of4-methyl-5-[2-(4-o-ethoxyphenylpiperazin-1-yl)ethyl]thiazole

The following are introduced into a 100 ml three-necked flask equippedwith a condenser, a pneumatic stirrer, a thermometer and a droppingfunnel:

41.26 g (0.2 mol) of 1-o-ethoxyphenylpiperazine

16.17 g (0.1 mol) of 4-methyl-5-β-chloroethylthiazole

The reaction medium is heated at 150° C. for 1 h.

After cooling to room temperature, it is poured into a 5% solution ofsodium bicarbonate.

The aqueous phase obtained is extracted with 3×150 ml of methylenechloride.

The combined organic phases are washed with a saturated aqueous solutionof sodium chloride and dried over sodium sulfate. After filtration, thesolvent is driven off under vacuum.

This gives 31.49 g of crude product (crude yield=95%). This is purifiedby fractional distillation under vacuum.

22.50 g of a brown liquid are isolated (yield after distillation=67.9%);b.p.₀.4 mm Hg =185°-190° C.; GC purity>99%.

2) Preparation of the trihydrochloride:

16.57 (0.05 mol) of this product are dissolved in anhydrous ethyl ether.

The solution is saturated with a stream of dry gaseous hydrochloric acidin an ice bath. The crystals formed are filtered off on a glass frit,washed with anhydrous ethyl ether and then dried under vacuum overpotassium hydroxide at 70° C.

This gives 19.24 g of beige crystals (crude yield=87.3%).

After recrystallization from a 1/3 isopropanol/ethanol mixture, 16.0 gof white crystals are isolated (yield after recrystallization=72.6%).

Said crystals have a melting point m.p._(KB) of 212°-213° C., IR and NMRspectra consistent with the proposed structure, a GC purity of >99% andan AgNO₃ titer of 100.2%.

EXAMPLE 2

Synthesis of4-methyl-5-[2-(4-o-hydroxyphenylpiperazin-1-yl)ethyl]thiazoledihydrochloride. Code name: B 1302. Product of formula (I) whereR=hydrogen, in the form of the dihydrochloride.

1) Preparation of4-methyl-5-[2-(4-o-hydroxyphenylpiperazin-1-yl)ethyl]thiazole

The following are introduced into a 100 ml three-necked flask equippedwith a condenser, a pneumatic stirrer, a thermometer and a droppingfunnel:

35.65 g (0.2 mol) of 1-o-hydroxyphenylpiperazine

16.17 g (0.1 mol) of 4-methyl-5-β-chloroethylthiazole

The reaction medium is heated at 150° C. for 1 h.

After cooling to room temperature and the addition of methylenechloride, it is poured into a saturated aqueous solution of sodiumchloride.

The organic phase is decanted and the aqueous phase is extracted with2×150 ml of methylene chloride.

The combined organic phases are washed with a saturated aqueous solutionof sodium chloride and dried over sodium sulfate. After filtration, thesolvent is driven off under vacuum.

This gives 27.61 g of a brown oil (crude yield=91%) having a GC purityof 97%.

2) Preparation of the dihydrochloride:

15 17 g (0.05 mol) of this crude product are dissolved in 430 ml ofanhydrous ethyl ether.

The solution is saturated with a stream of dry gaseous hydrochloric acidin an ice bath.

The crystals formed are filtered off on a glass frit, washed withanhydrous ethyl ether and then dried under vacuum over potassiumhydroxide at 70° C.

This gives 18.06 g of beige crystals (crude yield=96%).

After two recrystallizations from a 1/1 isopropanol/methanol mixture,4.80 g of light beige crystals are isolated (yield afterrecrystallizations=25.5%).

Said crystals have a melting point m.p._(KB) of 250°-255° C., IR and NMRspectra consistent with the proposed structure and an AgNO₃ titer of100.5%.

EXAMPLE 3

Synthesis of4-methyl-5-[2-(4-o-butoxyphenylpiperazin-1-yl)ethyl]thiazolemonohydrochloride. Code name: B 1341. Product of formula (I) whereR=butyl, in the form of the monhydrochloride

1) Preparation of4-methyl-5-[2-(4-o-butoxyphenylpiperazin-1-yl)ethyl]thiazole

The following are introduced into a 100 ml three-necked flask equippedwith a condenser, a pneumatic stirrer, a thermometer and a droppingfunnel:

46.87 g (0.2 mol) of 1-o-butoxyphenylpiperazine

16.17 g (0.1 mol) of 4-methyl-5-β-chloroethylthiazole

The reaction medium is heated at 150° C. for 1 h.

After cooling to room temperature and the addition of ethyl ether, it ispoured into H₂ O. The organic phase is decanted and the remainingaqueous phase is extracted with twice 150 ml of ethyl ether. Thecombined organic phases are washed with a saturated aqueous solution ofsodium chloride and dried over sodium sulfate. After filtration, thesolvent is driven off under vacuum.

This gives 33.76 g of a brown oil (crude yield=93.9%), which is purifiedby fractional distillation under vacuum.

24.16 g of an orange liquid are isolated (yield afterdistillation=67.2%); b.p.₀.1 mm Hg =180°-185° C.; GC purity=98.8%.

2) Preparation of the monohydrochloride:

17.97 g (0.05 mol) of this product are dissolved in absolute ethanol.

After cooling in an ice bath, 43.5 ml of an ethanolic solution of HCl(containing 1.15 mol of HCl per liter) are added.

After stirring for 30 min, the mixture is concentrated to dryness undervacuum and the residue is taken up with anhydrous ether.

The crystals formed are filtered off on a glass frit, washed withanhydrous ethyl ether and then dried under vacuum over potassiumhydroxide at 70° C.

This gives 19.16 of beige crystals (crude yield=96.8%).

After recrystallization from isopropanol, 16.06 g of white crystals areisolated (yield after recrystallization=81.1%).

Said crystals have a melting point m.p._(KB) of 180°-185° C., IR and NMRspectra consistent with the proposed structure, an AgNO₃ titer of 98.6%and a GC purity of >99.5%.

EXAMPLE 4

Synthesis of4-methyl-5-[2-(4-o-pentoxyphenylpiperazin-1-yl)ethyl]thiazolemonohydrochloride. Code name: B 1357. Product of formula (I) whereR=pentyl, in the form of the monohydrochloride.

1) Preparation of4-methyl-5-[2-(4-o-pentoxyphenylpiperazin-1-yl)ethyl]thiazole

The following are introduced into a 100 ml three-necked flask equippedwith a condenser, a pneumatic stirrer and a thermometer:

27.32 g (0.11 mol) of 1-o-pentoxyphenylpiperazine

8.89 g (0.055 mol) of 4-methyl-5-β-chloroethylthiazole

The reaction medium is heated at 150° C. for 1 h 30 min.

After cooling to room temperature and the addition of 200 ml of ethylether, it is poured into 200 ml of H₂ O. The organic phase is decantedand the remaining aqueous phase is extracted with twice 100 ml of ethylether. The combined organic phases are washed with a saturated aqueoussolution of sodium chloride and dried over sodium sulfate. Afterfiltration, the solvent is driven off under vacuum.

This gives 19.04 g of a brown oil (crude yield=92.6%), which is purifiedby fractional distillation under vacuum.

13.25 g of an orange liquid are isolated (yield afterdistillation=64.5%).

B.p.₀.1 mm Hg =190°-193° C.; GC purity=99.9%; perchloric titer=100.6%.

2) Preparation of the monohydrochloride

12.44 g (0.0333 mol) of this product are dissolved in 150 ml of absoluteethanol. The solution is cooled in an ice bath and 23.1 ml of anethanolic solution of HCl (containing 1.44 mol of HCl per liter) areadded.

After stirring for 5 min, the mixture is concentrated to dryness undervacuum and the residue is taken up with anhydrous ethyl ether.

The crystals formed are filtered off on a glass frit, washed with ethylether and then dried under vacuum over potassium hydroxide at 70° C.

This gives 13.38 g of beige crystals (crude yield: 98%).

After recrystallization from an ethyl acetate/isopropanol mixture(20/1), 10.35 g of white crystals are isolated (yield afterrecrystallization=75.8%).

Said crystals have a melting point m.p._(KB) of 156°-158° C., IR and NMRspectra consistent with the proposed structure, an AgNO₃ titer of 97.7%and a GC purity of 99.9%.

EXAMPLE 5

Synthesis of4-methyl-5-[2-(4-o-isopropoxyphenylpiperazin-1-yl)ethyl]thiazolemonohydrochloride. Code name: B 1398. Product of formula (I) whereR=isopropyl, in the form of the monohydrochloride.

1) Preparation of4-methyl-5-[2-(4-o-isopropoxyphenylpiperazin-1-yl)ethyl]thiazole

The following are introduced into a 100 ml three-necked flask equippedwith a condenser, a pneumatic stirrer and a thermometer:

29.41 g (0.133 mol) of 1-o-isopropoxyphenylpiperazine

10 g (0.062 mol) of 4-methyl-5-β-chloroethylthiazole

The reaction medium is heated at 150° C. for 1 h.

After cooling to room temperature and the addition of methylenechloride, it is poured into a 10% solution of NaHCO₃. The organic phaseis decanted and the remaining aqueous phase is extracted with twice 100ml of CH₂ Cl₂. The combined organic phases are washed with a saturatedaqueous solution of sodium chloride until the washings are neutral, anddried over sodium sulfate. After filtration, the solvent is driven offunder vacuum.

This gives a crude oil containing the excess of1-o-isopropoxyphenylpiperazine which has served as an HCl acceptor.Purification is effected by fractional distillation under vacuum.

17.2 g of an orange liquid are isolated (yield afterdistillation=80.5%).

B.p.₀.15 mm Hg =225°-230° C.; GC purity=99%.

2) Preparation of the monohydrochloride

17.2 g (0.05 mol) of this product are dissolved in absolute ethanol.

After cooling in an ice bath, 37 ml of an ethanolic solution of HCl(containing 1.35 mol of HCl per liter) are added.

After stirring for 5 min, the precipitate thus formed is filtered off ona glass frit, washed with anhydrous ethyl ether and then dried undervacuum over potassium hydroxide at 70° C.

This gives 13.9 g of white crystals (crude yield: 72.7%).

After recrystallization from an ethyl acetate/ethanol mixture (3/1),11.6 g of white crystals are isolated (yield after recrystallization:60.6%).

Said crystals have a melting point m.p._(KB) of 196°-200° C., IR and NMRspectra consistent with the proposed structure, an AgNO₃ titer of 98%and a GC purity of 99.9%.

EXAMPLE 6

Synthesis of4-methyl-5-[2-(4-o-methoxyphenylpiperazin-1-yl)ethyl]thiazoletrihydrochloride. Code name: B 1433. Product of formula (I) whereR=methyl.

1) Preparation of4-methyl-5-[2-(4-o-methoxyphenylpiperazin-1-yl)ethyl]thiazole

The following are introduced into a 500 ml three-necked flask equippedwith a condenser, a pneumatic stirrer, a thermometer and a droppingfunnel:

210 ml of butan-1-ol

10.66 (0.0554 mol) of 1-o-methoxyphenylpiperazine

in portions, 8.81 g (0.0831 mol) of anhydrous Na₂ CO₃.

8.96 (0.0554 mol) of 4-methyl-5-β-chloroethylthiazole are addeddropwise.

The reaction medium is refluxed for 50 h.

After hot filtration of the reaction medium and washing of the insolublesalts with ethanol, the filtrate is concentrated to dryness undervacuum.

This gives 15.2 g of a brown oil (crude yield: 86.4%) having a GC purityof 94.2%.

2) Preparation of the trihydrochloride

14.5 g (0.0457 mol) of this product are dissolved in 80 ml of anhydrousethyl ether.

After cooling in an ice bath, the solution is saturated with gaseous HClby bubbling.

The mixture is stirred for 15 min. The crystals formed are filtered offon a glass frit, washed with anhydrous ethyl ether and then dried undervacuum over potassium hydroxide at 70° C.

This gives 17.06 g of crystals (crude yield: 87.5%).

After recrystallization from 330 ml of ethanol, 9 g of white crystalsare isolated (yield after recrystallization=46.2%).

Said crystals have a melting point m.p._(KB) of 210°-212° C., IR and NMRspectra consistent with the proposed structure, an AgNO₃ titer of 96.5%and a GC purity of 99.9%.

EXAMPLES 7 TO 11

Experimental procedures similar to those just described, which thoseskilled in the art will easily be able to work out, were used to preparethe compounds of formula (I) in which R is respectively a propyl radical(Example 7), an isobutyl radical (Example 8), an isopentyl radical(Example 9), a neopentyl radical (Example 10) and a benzyl radical(Example 11).

The formulae and the physical properties of the products synthesized inExamples 1 to 11 have been collated in Summary Table no. 1.

The toxicity and the pharmacological properties of the products offormula I were tested; the results obtained are described below.

1) Acute toxicity in mice:

Principle of the measurement

The products were administered orally, in a single dose, to male micewith an average weight of 22 g. The mortality was recorded after anobservation period of 14 days.

The results are expressed in the form of the 50% lethal dose (LD₅₀),i.e. the theoretical dose in mg.kg⁻¹, administered orally, which causesthe death of 50% of the animals.

Results

These are reported in Table 2.

Virtually all the molecules have an LD₅₀ of more than 1 g.kg⁻¹. Theseproducts therefore have a low toxicity after a single administration.

2) Determination of the alpha-blockinq activity on isolated rat vasdeferens

a) Principle of the measurement

Stimulation of the post-synaptic alpha-adrenergic receptors bynorepinephrine causes contraction of the isolated vas deferens.

The concentration of product in whose presence the norepinephrineconcentration must be doubled to obtain the same effect as in theabsence of said product is determined.

The logarithm of this concentration, with its sign changed, constitutesthe pA₂ of the products.

b) Results obtained

The pA₂ values reported in Table 3 show that the products behave ascompetitive norepinephrine antagonists at the alpha-adrenergicreceptors.

Their alpha-blocking activity is high since it appears for lowconcentrations of between 2.10⁻⁷ M and 10⁻⁸ M.

3) Determination of the adrenolytic activity "in vivo" in rats:

a) Principle of the measurement

The intravenous injection of norepinephrine (0.4 mg.kg⁻¹) into wake ratscauses the death of 100% of the animals. The prior administration of asubstance with an alpha-blocking property enables this toxicity to bereduced.

The results are expressed in the form of the 50% effective dose (ED₅₀),i.e. the dose in mg.kg⁻¹ which protects 50% of the animals.

b) Results obtained

The ED₅₀ values corresponding to the products of Examples 1 to 11 areshown in Table 4.

The majority of the products are active at relatively low doses. Theiradrenolytic activity in the whole animal is therefore very high, thusconfirming the effects demonstrated in vitro.

It should be noted that the ED₅₀ of all these compounds is veryconsiderably lower (a gain of about 40% to about 90%) than that of4-methyl-5-[2-(4-phenylpiperazin-1-yl)ethyl]thiazole (which is 8.7mg.kg⁻¹ under the same conditions).

These results show the value of these compounds and their distinctsuperiority over the most similar compound of the state of the art.

4) Determination of the inhibitory action of the compounds towards theincrease in ureteral pressure induced in rabbits by the intravenousadministration of norepinephrine

a) Principle of the measurement

The ureteral pressure is measured by catheterization of the prostaticureter of anesthetized male rabbits. The increase in ureteral pressureis induced by an intravenous injection of norepinephrine. Thishyperpressure can be inhibited by the prior administration of moleculeswith alpha-blocking potential.

B 1211, B 1302, B 1341, B 1357, B 1398 and B 1433 were the onlycompounds to be tested on this model.

b) Results obtained

These are shown in Table 5 in the form of the 50% inhibitory dose(ID₅₀), which is defined as being the dose of product which, whenadministered intravenously, causes a 50% inhibition of the ureteralhyperpressure induced by norepinephrine.

The compounds tested are particularly effective with active doses ofless than 1 mg.kg⁻¹.

B 1398 is remarkably effective.

These data make it possible to predict a good therapeutic activity forthese molecules in functional dysuria associated with hyperactivity ofthe alpha-adrenergic sympathetic nervous system.

The products can be administered by a general route (parenterally,orally, rectally) or topically.

The pharmaceutical compositions in which at least one product accordingto the invention is present as the active ingredient, in combinationwith a pharmaceutically acceptable vehicle, can be solid or liquid andcan take the form of, for example, injectable preparations, tablets,gelatin capsules or granules. The dosage can vary within wide limits,depending in particular on the type and severity of the complaint to betreated and on the mode of administration.

Most frequently, the adult dosage is between 0.05 and 0.5 g per day byparenteral administration and between 0.1 and 4 g per day by oraladministration.

                                      TABLE 1                                     __________________________________________________________________________    GENERAL FORMULA:                                                               ##STR3##                                                                     Example                                                                            R          n B code                                                                            Empirical formula                                                                      MW  M.p..sub.KB (°C.)                   __________________________________________________________________________    1    C.sub.2 H.sub.5                                                                          3 1211                                                                              C.sub.18 H.sub.28 Cl.sub.3 N.sub.3 OS                                                  440.85                                                                            212-213                                    2    H          2 1302                                                                              C.sub.16 H.sub.23 Cl.sub.2 N.sub.3 OS                                                  376.35                                                                            250-255                                    3    (CH.sub.2).sub.3CH.sub.3                                                                 1 1341                                                                              C.sub.20 H.sub.30 ClN.sub.3 OS                                                         396.0                                                                             180-185                                    4    (CH.sub.2).sub.4CH.sub.3                                                                 1 1357                                                                              C.sub.21 H.sub.32 ClN.sub.3 OS                                                         410.04                                                                            156-158                                    7    (CH.sub.2).sub.2CH.sub.3                                                                 1 1359                                                                              C.sub.19 H.sub.28 ClN.sub.3 OS                                                         381.96                                                                            189-190                                          ##STR4##  1 1398                                                                              C.sub.19 H.sub.28 ClN.sub.3 OS                                                         381.96                                                                            196-200                                    8                                                                                   ##STR5##  1 1422                                                                              C.sub.20 H.sub.30 ClN.sub.3 OS                                                         395.95                                                                            188-189                                    9                                                                                   ##STR6##  1 1423                                                                              C.sub.21 H.sub.32 ClN.sub.3 OS                                                         410.04                                                                            160-162                                    10                                                                                  ##STR7##  1 1424                                                                              C.sub.21 H.sub.32 ClN.sub.3 OS                                                         410.04                                                                            200-202                                    11                                                                                  ##STR8##  2 1425                                                                              C.sub.23 H.sub.29 Cl.sub.2 N.sub.3 OS                                                  466.45                                                                            175-180                                    6    CH.sub.3   3 1433                                                                              C.sub.17 H.sub.26 Cl.sub.3 N.sub.3 OS                                                  426.82                                                                            210-212                                    __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    ACUTE TOXICITY OF THE COMPOUNDS IN MICE AFTER A SINGLE ORAL                   ADMINISTRATION (LD.sub.50 = 50 percent lethal dose)                                   B code                                                                        1211                                                                              1302                                                                             1341                                                                              1357                                                                              1359                                                                              1398                                                                              1422                                                                              1423                                                                              1424                                                                              1425                                                                              1433                           __________________________________________________________________________    LD.sub.50                                                                             >1000                                                                             490                                                                              >1000                                                                             >1000                                                                             >1000                                                                             >1000                                                                             >1000                                                                             >1000                                                                             >1000                                                                             >1000                                                                             >1000                          mg · kg.sup.-1 p.o.                                                  __________________________________________________________________________

                                      TABLE 3                                     __________________________________________________________________________    ALPHA-BLOCKING ACTIVITY OF THE COMPOUNDS TOWARDS                              NOREPINEPHRINE ON ISOLATED RAT VAS DEFERENS                                   B code                                                                        1211   1302                                                                             1341                                                                             1357                                                                             1359                                                                             1398                                                                             1422                                                                             1423                                                                             1424                                                                             1425                                                                             1433                                        __________________________________________________________________________    pA.sub.2                                                                          7.58                                                                             6.90                                                                             8.0                                                                              7.77                                                                             7.24                                                                             7.77                                                                             7.44                                                                             7.34                                                                             6.7                                                                              7.20                                                                             7.84                                        __________________________________________________________________________

                                      TABLE 4                                     __________________________________________________________________________    ADRENOLYTIC ACTIVITY OF THE COMPOUNDS TOWARDS THE                             LETHAL EFFECT OF NOREPINEPHRINE IN RATS BY                                    ORAL ADMINISTRATION (ED.sub.50 = 50 percent effective dose)                           B code                                                                        1211                                                                             1302                                                                             1341                                                                             1357                                                                             1359                                                                             1398                                                                             1422                                                                             1423                                                                             1424                                                                             1425                                                                             1433                                    __________________________________________________________________________    ED.sub.50                                                                             2  4  1  1.80                                                                             1.93                                                                             0.44                                                                             1.60                                                                             2.35                                                                             2.04                                                                             5  2.66                                    mg · kg.sup.-1 p.o.                                                  __________________________________________________________________________

                                      TABLE 5                                     __________________________________________________________________________    INHIBITORY ACTION OF THE COMPOUNDS ON THE INCREASE IN                         URETERAL PRESSURE INDUCED IN RABBITS BY THE INTRAVENOUS                       ADMINISTRATION OF NOREPINEPHRINE                                              (ID.sub.50 : 50 percent inhibitory dose)                                             B code                                                                        1211                                                                             1302                                                                             1341                                                                             1357                                                                             1359                                                                             1398                                                                             1422                                                                             1423                                                                             1424                                                                             1425                                                                             1433                                     __________________________________________________________________________    ID.sub.50                                                                            0.16                                                                             0.44                                                                             0.39                                                                             0.46                                                                             -- 0.09                                                                             -- -- -- -- 0.3                                      mg · kg.sup.-1 i.v.                                                  __________________________________________________________________________

What is claimed is:
 1. A 4-methyl-5-thiazole compound of the formula##STR9## in which R is selected from the group consisting of a hydrogenatom, an alkyl radical having from 2 to 7 carbon atoms and an aralkylradical of which the aryl moiety consists of phenyl or naphthyl, oroptionally lower alkyl substituted phenyl or naphthyl and of which thealkyl moiety has from 1 to 4 carbon atoms, or a pharmaceuticallyacceptable salt thereof.
 2. A compound according to claim 1, wherein Ris selected from the group consisting of a hydrogen atoms, a methylradical, an ethyl radical, an isopropyl radical, a butyl radical and apentyl radical.
 3. A pharmaceutical composition for the treatment offunctional dysuria associated with hyperactivity of the -adrenergicsympathetic nervous system, said composition containing an effectiveamount of at least one compound according to claim 8 as the activeingredient, in combination with a pharmaceutically acceptable vehicle,excipient or carrier.
 4. A pharmaceutical composition for the treatmentof functional dysuria associated with hyperactivity of the -adrenergicsympathetic nervous system, said composition containing an effectiveamount of at least one compound according to claim 2 as the activeingredient, in combination with a pharmaceutically acceptable vehicle,excipient or carrier.
 5. A 4-methyl-5-thiazole compound of the formula##STR10## in which R is selected from the group consisting of a hydrogenatom, an alkyl radical having from 2 to 7 carbon atoms, an aralkylradical or a pharmaceutically acceptable salt thereof.
 6. A compoundaccording to claim 5, wherein R is selected from the group consisting ofa hydrogen atom, an ethyl, an isopropyl, a butyl and a pentyl radical.7. A pharmaceutical composition for the treatment of functional dysuriaassociated with hyperactivity of the -adrenergic sympathetic nervoussystem, said composition containing an effective amount of at least onecompound according to claim 5 as the active ingredient, in combinationwith a pharmaceutically acceptable vehicle, excipient or carrier.
 8. Amethod of treating functional dysuria associated with hyperactivity ofthe -adrenergic sympathetic nervous system, which comprisesadministering an effective amount of at least one compound according toclaim 1, or a pharmaceutically acceptable salt thereof.
 9. A method oftreating functional dysuria associated with hyperactivity of the-adrenergic sympathetic nervous system, which comprises administering aneffective amount of at least one compound according to claim 5, or apharmaceutically acceptable salt thereof.
 10. A method of treatingfunctional dysuria associated with hyperactivity of the -adrenergicsympathetic nervous system, which comprises administering an effectiveamount of 4-methyl-5-thiazole or a pharmaceutically acceptable saltthereof.